Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.

Disease exacerbations and muscle wasting comprise negative prognostic factors of chronic obstructive pulmonary disease (COPD). Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting after acute exacerbations of COPD. However, the interactions between systemic inflammation and malnutrition in their contributions to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy, remain unresolved. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS to model acute disease exacerbation. Systemic inflammation, nutritional intake, and body and muscle weights were determined. Muscle inflammatory signaling and atrophy signaling were examined, and the effect of the muscle-specific inactivation of NF-κB on muscle atrophy was assessed in genetically modified mice. The intratracheal LPS instillation was followed by markedly elevated circulating cytokine concentrations and NF-κB activation in extrapulmonary tissues, including skeletal muscle. The administration of intratracheal LPS increased the expression of muscle E3 ubiquitin ligases, which govern muscle proteolysis, in particular MuRF1, and caused a rapid loss of muscle mass. Reduced food intake only partly accounted for the observed muscle atrophy, and did not activate NF-κB in muscle. Rather, plasma transfer experiments revealed the presence of NF-κB–signaling and atrophy-signaling properties in the circulation of intratracheal LPS–treated mice. The genetic inhibition of muscle NF-κB activity suppressed intratracheal LPS–induced MuRF1 expression and resulted in a significant sparing of muscle tissue. Systemic inflammation and malnutrition contribute to the muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-κB activation is required for the transition from inflammatory to muscle atrophy signaling.

Background: Cachexia, highly prevalent in patients with non‐small cell lung cancer (NSCLC), impairs quality of life and is associated with reduced tolerance and responsiveness to cancer therapy and decreased survival. MicroRNAs (miRNAs) are small non‐coding RNAs that play a central role in post‐transcriptional gene regulation. Changes in intramuscular levels of miRNAs have been implicated in muscle wasting conditions. Here, we aimed to identify miRNAs that are differentially expressed in skeletal muscle of cachectic lung cancer patients to increase our understanding of cachexia and to allow us to probe their potential as therapeutic targets.Methods: A total of 754 unique miRNAs were profiled and analysed in vastus lateralis muscle biopsies of newly diagnosed treatment‐naïve NSCLC patients with cachexia (n = 8) and age‐matched and sex‐matched healthy controls (n = 8). miRNA expression analysis was performed using a TaqMan MicroRNA Array. In silico network analysis was performed on all significant differentially expressed miRNAs. Differential expression of the top‐ranked miRNAs was confirmed using reverse transcription–quantitative real‐time PCR in an extended group (n = 48) consisting of NSCLC patients with (n = 15) and without cachexia (n = 11) and healthy controls (n = 22). Finally, these miRNAs were subjected to univariate and multivariate Cox proportional hazard analysis using overall survival and treatment‐induced toxicity data obtained during the follow‐up of this group of patients.Results: We identified 28 significant differentially expressed miRNAs, of which five miRNAs were up‐regulated and 23 were down‐regulated. In silico miRNA‐target prediction analysis showed 158 functional gene targets, and pathway analysis identified 22 pathways related to the degenerative or regenerative processes of muscle tissue. Subsequently, the expression of six top‐ranked miRNAs was measured in muscle biopsies of the entire patient group. Five miRNAs were detectable with reverse transcription–quantitative real‐time PCR analysis, and their altered expression (expressed as fold change, FC) was confirmed in muscle of cachectic NSCLC patients compared with healthy control subjects: miR‐424‐5p (FC = 4.5), miR‐424‐3p (FC = 12), miR‐450a‐5p (FC = 8.6), miR‐144‐5p (FC = 0.59), and miR‐451a (FC = 0.57). In non‐cachectic NSCLC patients, only miR‐424‐3p was significantly increased (FC = 5.6) compared with control. Although the statistical support was not sufficient to imply these miRNAs as individual predictors of overall survival or treatment‐induced toxicity, when combined in multivariate analysis, miR‐450‐5p and miR‐451a resulted in a significant stratification between short‐term and long‐term survival.Conclusions: We identified differentially expressed miRNAs putatively involved in lung cancer cachexia. These findings call for further studies to investigate the causality of these miRNAs in muscle atrophy and the mechanisms underlying their differential expression in lung cancer cachexia.

Cancer is the second leading cause of death worldwide and the global cancer burden rises rapidly. The risk factors for cancer development can often be attributed to lifestyle factors, of which an unhealthy diet is a major contributor. Dietary fat is an important macronutrient and therefore a crucial part of a well-balanced and healthy diet, but it is still unclear which specific fatty acids contribute to a healthy and well-balanced diet in the context of cancer risk and prognosis. In this review, we describe epidemiological evidence on the associations between the intake of different classes of fatty acids and the risk of developing cancer, and we provide preclinical evidence on how specific fatty acids can act on tumor cells, thereby modulating tumor progression and metastasis. Moreover, the pro- and anti-inflammatory effects of each of the different groups of fatty acids will be discussed specifically in the context of inflammation-induced cancer progression and we will highlight challenges as well as opportunities for successful application of fatty acid tailored nutritional interventions in the clinic.